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inflammation include gastric ulcer, gastric metaplasia of the duodenal bulb, duodenitis, and ultimately duodenal ulcer. A long-standing infection may lead to intestinal metaplasia and gastric carcinoma. Recently, B-cell lymphomas of the stomach have also been associated with HP.

Issues in Vaccine Development. Because HP is a noninvasive surface infection, vaccines should elicit strong mucosal or secretory IgA immunity against one or more prominent surface proteins of the bacterium. Because HP has several virulence factors, the vaccine should be designed to prevent infection rather than interfere with just one virulence factor. Because the infection persists despite a vigorous immune response by the host, and hosts cured of infection with antibiotics appear to be susceptible to reinfection or recrudescence, natural immunity does not seem to be sufficient to protect against or clear infection; hence the vaccine should elicit a response that is qualitatively or quantitatively different from natural immunity.

In addition, HP antigens may elicit hypersensitivity or autoreactive responses, as was the case with Group A streptococci; for this reason, the vaccine should be based on a well-characterized protein that avoids these reactions. The latter considerations—inadequacy of natural immunity and potential crossreactions—argue against the use of live attenuated vaccines or crude whole-cell preparations.

Finally, HP strains are extremely plastic, showing wide variation at both the genomic and antigenic levels. Consequently, the antigen or antigens used in a vaccine must be highly conserved and must be expressed in vivo, so as to be available as a target for immune response. Several candidate antigens have been investigated, including urease and vacuolating cytotoxin, and the ultimate vaccine may involve a combination of antigens. The balance of the presentation focused on urease.

Urease-Based Prophylactic Vaccine. Urease is an abundant protein on the surface of the bacteria and makes up over 6 percent of its total soluble protein. It is highly conserved across strains of HP and even across different species of Helicobacter that can be used in animal models (see below). It is a large molecule (550 kD) with a particulate structure, but natural immunity to HP includes only a weak or inconsistent response to urease. The enzyme functions as a virulence factor: it splits the urea found in gastric secretions into two molecules of ammonia, creating a neutralizing cloud around that bacteria that protects it as it passes through the acid environment of the stomach on its way to the pH-neutral environment under the mucous lining.

The operon that controls urease includes two structural genes, ure-A and ure-B, that code for proteins of about 25 and 60 kD respectively. Six units of each of these proteins make up the intact 550-kD molecule. The rest of the genes in this operon are involved in folding the molecule in such a way as to incorporate a molecule of nickel, the metalloenzyme required for its activity. By cloning the two structural genes and leaving out the rest, researchers were able to generate a recombinant urease that is structurally and antigenically intact but lacks the enzymatic activity that would be harmful to a host. Cloned into E. coli



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